Skip to main content
SpringerLink
Log in

T Cell Tolerance to Tumors and Cancer Immunotherapy

  • Conference paper
Immune-Mediated Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 601))

Abstract

It is widely recognized that the immune system plays a role in cancer progression and that some tumors are inherently immunogenic. The identification of tumor-associated antigens (TAAs) has stimulated research focused on immunotherapies to mediate the regression of established tumors. Cancer-specific immunity has traditionally been aimed at activating CD8+ cytotoxic T lymphocytes (CTLs) directed against major histocompatibility complex (MHC) class I-binding peptide epitopes. Other approaches utilize T cell adoptive therapy where autologous, tumor-specific T cells propagated in vitro are transferred back into recipients. However, these strategies have met with limited success in part due to the regulatory mechanisms of T cell tolerance, which poses a considerable challenge to cancer immunotherapy. Our laboratory utilizes the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model, a murine model of prostate cancer, to study mechanisms of T cell tolerization to tumor antigens. We previously demonstrated that upon encounter with their cognate antigen in the tumor microenvironment, naïve T cell become tolerized. Our ongoing studies are testing whether provision of CD4+ T cells can enhance tumor immunity by preventing CD8+ T cell tolerance. A greater understanding of the interaction between various tumor-specific T cell subsets will facilitate the design of novel approaches to stimulate a more potent antitumor immune response.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Abken, H., Hombach, A., Heuser, C., Kronfeld, K. and Seliger, B. (2002) Tuning tumor-specific T cell activation: a matter of costimulation? Trends Immunol 23, 240–245.

    Article  PubMed  CAS  Google Scholar 

  • Anderson, M., Shafer-Weaver, K., Greenberg, N. and Hurwitz, A. (2007) Tolerization of tumor-specific T cells despite efficient initial priming in a primary murine model of prostate cancer. J Immunol 178, 1268–1276.

    PubMed  CAS  Google Scholar 

  • Attia, P., Maker, A., Haworth, L., Rogers-Freezer, L. and Rosenberg, S. (2005a) Inability of a fusion protein of IL-2 and diphtheria toxin to eliminate regulatory T lymphocytes in patients with melanoma. J Immunother 28, 582–592.

    Article  PubMed  CAS  Google Scholar 

  • Attia, P., Phan, G., Maker, A., Robinson, M.,Quezado, M., Yang, J., Sherry, R., Topalian, S., Kammula, U., Royal, R., Restifo, N., Haworth, L., Levy, C., Mavroukakis, S., Nichol, G., Yellin, M. and Rosenberg, S. (2005b) Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 23, 6043–6053.

    Article  PubMed  CAS  Google Scholar 

  • Barnett, B., Kryczek, I., Cheng, P., Zou, W. and Curiel, T. (2005) Regulatory T cells in ovarian cancer: biology and therapeutic potential. Am J Reprod Immunol 54, 369–377.

    Article  PubMed  CAS  Google Scholar 

  • Bennett, S., Carbone, F., Karamalis, F., Flavell, R., Miller, J. and Heath, W. (1998) Help for cytotoxic-T cell responses is mediated by CD40 signalling. Nature 393, 478–480.

    Article  PubMed  CAS  Google Scholar 

  • Berkow, R. and Beers, M. (1997). Cancer and the immune system. The Merck Manual of Medical Information. Whitehouse Station, Merck Research Laboratories:792–794.

    Google Scholar 

  • Blattman, J. and Greenberg, P. (2004) Cancer immunotherapy: a treatment for the masses. Science 305, 200–205.

    Article  PubMed  CAS  Google Scholar 

  • Bogen, B. (1996) Peripheral T cell tolerance as a tumor escape mechanism: deletion of CD4+ T cells specific for a monoclonal immunoglobulin idiotype secreted by a plasmacytoma. Eur J Immunol 26, 2671–2679.

    Article  PubMed  CAS  Google Scholar 

  • Boon, T. and van der Bruggen, P. (1996) Human tumor antigens recognized by T lymphocytes. J Exp Med 183, 725–729.

    Article  PubMed  CAS  Google Scholar 

  • Boshoff, C. and Weiss, R. (2002) AIDS-related malignancies. Nat Rev Cancer 2, 373–382.

    Article  PubMed  CAS  Google Scholar 

  • Challis, G. and Stam, H. (1990) The spontaneous regression of cancer. A review of cases from 1900 to 1987. Acta Oncol 29, 545–550.

    Article  PubMed  CAS  Google Scholar 

  • Chen, Q., Daniel, V. and Maher, D. (1994) Production of IL-10 by melanoma cells: examination of its role in immunosuppression mediated by melanoma. Int J Cancer 56, 755–760.

    Article  PubMed  CAS  Google Scholar 

  • Comes, A., Rosso, O., Orengo, A., Carlo, E.D., Sorrentino, C., Meazza, R., Piazza, T., Valzasina, B., Nanni, P., Colombo, M. and Ferrini, S. (2006) CD25+ regulatory T cell depletion augments immunotherapy of micrometastases by an IL-21-secreting cellular vaccine. J Immunol 176, 1750–1758.

    PubMed  CAS  Google Scholar 

  • Conejo-Garcia, J., Benencia, F., Courreges, M., Kang, E., Mohamed-Hadley, A., Buckanovich, R., Holtz, D., Jenkins, A., Na, H., Wagner, D., Katsaros, D., Caroll, R. and Coukos, G. (2004) Tumor-infiltrating dendritic cell precursors recruited by a beta-defensin contribute to vasculogenesis under the influence of Vegf-A. Nat Med 10, 950–958.

    Article  PubMed  CAS  Google Scholar 

  • Cretney, E., Takeda, K., Yagita, H., Glaccum, M., Peschon, J. and Smyth, M. (2002) Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J Immunol 168, 1356–1361.

    PubMed  CAS  Google Scholar 

  • Curiel, T., Coukos, G., Zou, L., Alvarez, X., Cheng, P., Mottram, P., Evdemon-Hogan, M., Conejo-Garcia, J., Zhang, L., Burow, M., Zhu, Y., Wei, S., Kryczek, I., Daniel, B., Gordon, A., Myers, L., Lackner, A., Disis, M., Knutson, K., Chen, L. and Zou, W. (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10, 942–949.

    Article  PubMed  CAS  Google Scholar 

  • Gabrilovich, D. (2004) Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol 4, 941–952.

    Article  PubMed  CAS  Google Scholar 

  • Gabrilovich, D., Ishida, T., Oyama, T., Ran, S., Kravtsov, V., Nadaf, S. and Carbone, D. (1998) Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92, 4150–4166.

    PubMed  CAS  Google Scholar 

  • Gattinoni, L., Klebanoff, C., Palmer, D., Wrzesinski, C., Kerstann, K., Yu, Z., Finkelstein, S., Theoret, M., Rosenberg, S. and Restifo, N. (2005) Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J Clin Invest 115, 1616–1626.

    Article  PubMed  CAS  Google Scholar 

  • Gorelik, L. and Flavell, R. (2001) Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 7, 1118–1122.

    Article  PubMed  CAS  Google Scholar 

  • Granziero, L., Krajewski, S., Farness, P., Yuan, L., Courtney, M., Jackson, M., Peterson, P. and Vitiello, A. (1999) Adoptive immunotherapy prevents prostate cancer in a transgenic animal model. Eur J Immunol 29, 1127–1138.

    Article  PubMed  CAS  Google Scholar 

  • Greenberg, N., DeMayo, F., Finegold, M., Medina, D., Tilley, W., Aspinall,J., Cunha, G., Donjacour, A., Matusik, R. and Rosen, J. (1995) Prostate cancer in a transgenic mouse. Proc Natl Acad Sci USA 92, 3439–3443.

    Article  PubMed  CAS  Google Scholar 

  • Huang, B., Pan, P., Li, Q., Sato, A., Levy, D., Bromberg, J., Divino, C. and Chen, S. (2006) Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced Treg cells and T cell anergy in tumor-bearing host. Cancer Res 66, 1123–1131.

    Article  PubMed  CAS  Google Scholar 

  • Hurwitz, A., Foster, B., Kwon, E., Truong, T., Choi, E., Greenberg, N., Burg, M. and Allison, J. (2000) Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade. Cancer Res 60, 2444–2448.

    PubMed  CAS  Google Scholar 

  • Hurwitz, A. and Ji, Q. (2004) Autoimmune depigmentation following sensitization to melanoma antigens. Methods Mol Med 102, 421–427.

    PubMed  CAS  Google Scholar 

  • Kalams, S. and Walker, B. (1998) The critical need for CD4 help in maintaining effective cytotoxic T lymphocyte responses. J Exp Med 188, 2199–2204.

    Article  PubMed  CAS  Google Scholar 

  • Kaplan, D., Shankaran, V., Dighe, A., Stockert, E., Aguet, M., Old, L. and Schreiber, R. (1998) Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci USA 95, 7556–7561.

    Article  PubMed  CAS  Google Scholar 

  • Khazaie, K. and von Boehmer, H. (2006) The impact of CD4+CD25+ Treg on tumor specific CD8+ T cell cytotoxicity and cancer. Semin Cancer Biol 16, 124–136.

    Article  PubMed  CAS  Google Scholar 

  • Krummel, M. and Allison, J.P. (1996) CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J Exp Med 183, 2533–2540.

    Article  PubMed  CAS  Google Scholar 

  • Linsley, P., Greene, J., Brady, W., Bajorath, J., Ledbetter, J. and Peach, R. (1994) Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1, 793–801.

    Article  PubMed  CAS  Google Scholar 

  • Liyanage, U., Moore, T. and Joo, H. (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169, 2756–2761.

    PubMed  CAS  Google Scholar 

  • Mapara, M. and Sykes, M. (2004) Tolerance and cancer: mechanisms of tumor evasion and strategies for breaking tolerance. J Clin Oncol 22, 1136–1151.

    Article  PubMed  CAS  Google Scholar 

  • Marzo, A., Kinnear, B., Lake, R., Frelinger, J., Collins, E., Robinson, B. and Scott, B. (2000) Tumor-specific CD4+ T cells have a major “post-licensing” role in CTL mediated anti-tumor immunity. J Immunol 165, 6047–6055.

    Google Scholar 

  • Mathis, D. and Benoist, C. (2004) Back to central tolerance. Immunity 20, 509–516.

    Article  PubMed  CAS  Google Scholar 

  • Melief, C. (2003) Regulation of cytotoxic T lymphocyte responses by dendritic cells: peaceful coexistence of cross-priming and direct priming? Eur J Immunol 33, 2645–2654.

    Article  PubMed  CAS  Google Scholar 

  • Miyara, M. and Sakaguchi, S. (2007) Natural regulatory T cells: mechanisms of suppression. Trends Mol Med. 13, 108–116.

    Article  PubMed  CAS  Google Scholar 

  • Molldrem, J., Lee, P., Kant, S., Wieder, E., Jiang, W., Lu, S., Wang, C. and Davis, M. (2003) Chronic myelogenous leukemia shapes host immunity by selective deletion of high-avidity leukemia-specific T cells. J Clin Invest 111, 639–647.

    PubMed  CAS  Google Scholar 

  • Moretti, S., Pinzi, C., Berti, E., Spallanzani, A., Chiarugi, A., Boddi, V., Reali, U. and Giannotti, B. (1997) In situ expression of transforming growthfactor beta is associated with melanoma progression and correlates with Ki67, HLA-DR and beta 3 integrin expression. Melanoma Res 7, 313–321.

    Article  PubMed  CAS  Google Scholar 

  • Moroz, A., Eppolito, C., Li, Q., Tao, J., Clegg, C. and Shrikant, P. (2004) IL-21 enhances and sustains CD8+ T cell responses to achieve durable tumor immunity: comparative evaluation of IL-2, IL-15, and IL-21. J Immunol 173, 900–909.

    PubMed  CAS  Google Scholar 

  • Naftzger, C., Takechi, Y., Kohda, H., Hara, I., Vijayasaradhi, S. and Houghton, A. (1996) Immune response to a differentiation antigen induced by altered antigen: a study of tumor rejection and autoimmunity. Proc Natl Acad Sci USA 93, 14809–14814.

    Article  PubMed  CAS  Google Scholar 

  • Naito, Y., Saito, K., Shiiba, K., Ohuchi, A., Saigenji, K., Nagura, H. and Ohtani, H. (1998) CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 58, 3491–3494.

    PubMed  CAS  Google Scholar 

  • Overwijk, W., Lee, D., Surman, D., Irvine, K., Touloukian, C., Chan, C., Carroll, M., Moss, B., Rosenberg, S. and Restifo, N. (1999) Vaccination with a recombinant vaccinia virus encoding a “self” antigen induces autoimmune vitiligo and tumor cell destruction in mice: requirement for CD4( + ) T lymphocytes. Proc Natl Acad Sci USA 96, 2982–2987.

    Article  PubMed  CAS  Google Scholar 

  • Rohrer, J., Barsoum, A. and Dyess, D. (1999) Human breast carcinoma patients develop clonable oncofetal antigen-specific effector and regulatory T lymphocytes. J Immunol , 162, 6880–6892.

    PubMed  CAS  Google Scholar 

  • Rosenberg, S. (1999) A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity 10, 281–287.

    Article  PubMed  CAS  Google Scholar 

  • Salazar-Onfray, F. (1999) Interleukin-10: a cytokine used by tumors to escape immunosurveillance. Med Oncol 16, 86–94.

    Article  PubMed  CAS  Google Scholar 

  • Schoenberger, S., Toes, R., Voort, E.v.d., Offringa, R. and Melief, C. (1998) T cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393, 480–483.

    Article  PubMed  CAS  Google Scholar 

  • Serafini, P., Borrello, I. and Bronte, V. (2006) Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol 16, 53–65.

    Article  PubMed  CAS  Google Scholar 

  • Sharma, S., Zhu, L., Yang, S., Zhang, L., Lin, J., Hillinger, S., Gardner, B., Reckamp, K., Strieter, R., Huang, M., Batra, R. and Dubinett, S. (2005) Cyclooxygenase 2 inhibition promotes IFN-gamma-dependent enhancement of antitumor responses. J Immunol 175, 813–819.

    PubMed  CAS  Google Scholar 

  • Shrikant, P., Khoruts, A. and Mescher, M. (1999) CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell- and IL-2-dependent mechanism. Immunity 11, 483–493.

    Article  PubMed  CAS  Google Scholar 

  • Smyth, M., Thia, K., Street, S., MacGregor, D., Godfrey, D. and Trapani, J. (2000) Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J Exp Med 192, 755–760.

    Article  PubMed  CAS  Google Scholar 

  • Sotomayor, E., Borrello, I., Rattis, F., Cuenca, A., Abrams, J., Staveley-O’Carroll, K. and Levitsky, H. (2001) Cross-presentation of tumor antigens by bone marrow-derived antigen-presenting cells is the dominant mechanism in the induction of T cell tolerance during B-cell lymphoma progression. Blood 98, 1070–1077.

    Article  PubMed  CAS  Google Scholar 

  • Staveley-O’Carroll, K., Sotomayor, E., Montgomery, J., Borrello, I., Hwang, L., Fein, S., Pardoll, D. and Levitsky, H. (1998) Induction of antigen-specific T cell anergy: An early event in the course of tumor progression. Proc Natl Acad Sci USA 95, 1178–1183.

    Article  PubMed  Google Scholar 

  • Sutmuller, R., Duivenvoorde, L.v., Elsas, A.v., Schumacher, T., Wildenberg, M., Allison, J., Toes, R., Offringa, R. and Melief, C. (2001) Synergism of CTLA-4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 194, 823–832.

    Article  PubMed  CAS  Google Scholar 

  • Takeda, K., Smyth, M., Cretney, E., Hayakawa, Y., Kayagaki, N., Yagita, H. and Okumura, K. (2002) Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. J Exp Med 195, 161–169.

    Article  PubMed  CAS  Google Scholar 

  • Tenderich, G., Deyerling, W. and Schulz, U. (2001) Malignant neoplastic disorders following long-term immunosuppression after orthotopic heart transplantation. Transplant. Proc 33, 3653–3655.

    Article  PubMed  CAS  Google Scholar 

  • Tourkova, I., Yamabe, K., Foster, B., Chatta, G., Perez, L., Shurin, G. and Shurin, M. (2004) Murine prostate cancer inhibits both in vivo and in vitro generation of dendritic cells from bone marrow precursors. Prostate 59, 203–213.

    Article  PubMed  Google Scholar 

  • Townsend, S. and Allison, J. (1993) Tumor rejection after direct costimulation of CD8+ T cells by B7-transfected melanoma cells. Science 259, 368–370.

    Article  PubMed  CAS  Google Scholar 

  • van Elsas, A., Hurwitz, A. and Allison, J. (1999) Combination immunotherapy of B16 melanoma using anti-CTLA-4 and GM-CSF-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med 190, 355–366.

    Article  PubMed  Google Scholar 

  • Ward, R., Hawkins, N., Coomber, D. and Disis, M. (1999) Antibody immunity to the HER-2/neu oncogenic protein in patients with colorectal cancer. Hum Immunol 60, 510–515.

    Article  PubMed  CAS  Google Scholar 

  • Yu, P., Lee, Y., Liu, W., Krausz, T., Chong, A., Schreiber, H. and Fu, Y. (2005) Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med 201, 779–791.

    Article  PubMed  CAS  Google Scholar 

  • Zheng, G., Liu, S., Wang, P., Xu, Y. and Chen, A. (2006) Arming tumor-reactive T cells with costimulator B7-1 enhances therapeutic efficacy of the T cells. Cancer Res 66, 6793–6799.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Applied and Developmental Research Support Program, SAIC-Frederick Inc., NCI-Frederick, Frederick, MD, USA

    Kimberly Shafer-Weaver & Anatoli Malyguine

  2. Tumor Immunity and Tolerance Section, Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, CCR, NIH, Frederick, MD, USA

    Michael Anderson & Arthur A. Hurwitz

Authors
  1. Kimberly Shafer-Weaver
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anatoli Malyguine
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arthur A. Hurwitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arthur A. Hurwitz .

Editor information

Editors and Affiliations

  1. Division of Clinical Immunopathology, 5725 Children’s Hospital of Pittsburgh, Main Tower, 200 Lothrop Street, Pittsburgh, PA, 15213, USA

    Michael R. Shurin (Associate Professor of Pathology and Immunology, Associate Director) (Associate Professor of Pathology and Immunology, Associate Director)

  2. Institute for Continuing Medical Education, Russian Association of Pediatric Allergology and Immunology, Clinical and Research Center of Allergy and Immunology, Ostrovitianova St., Bldg. 6, Moscow, 117513, Russia

    Yuri S. Smolkin (Professor of Immunology, Vise-President, Director) (Professor of Immunology, Vise-President, Director)

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Springer Science+Business Media, LLC

About this paper

Cite this paper

Shafer-Weaver, K., Anderson, M., Malyguine, A., Hurwitz, A.A. (2007). T Cell Tolerance to Tumors and Cancer Immunotherapy. In: Shurin, M.R., Smolkin, Y.S. (eds) Immune-Mediated Diseases. Advances in Experimental Medicine and Biology, vol 601. Springer, New York, NY. https://doi.org/10.1007/978-0-387-72005-0_38

Download citation

Publish with us

Policies and ethics

Search

Navigation